Title

Author

Date of Award

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Ding Xue

Second Advisor

Dylan Taatjes

Third Advisor

Amy Palmer

Fourth Advisor

Xuedong Liu

Fifth Advisor

Hang Yin

Abstract

The round worm, Caenorhabditis elegans, provides a simple system to study complex questions. The philosophy behind it is that a single cell contains almost all of the components that make up life, even as complex as a human. I studied two conserved and fundamental biological topics over the span of the past 6 years: programmed cell death, and paternal mitochondrial elimination (PME). Programmed cell death (apoptosis) is the process by which individual cells sacrifice themselves for the good of the organism. Cells undergo apoptosis in a finely regulated fashion. Using C. elegans, I investigated the regulatory mechanism of CED-8, an apoptotic executor that not only mediates PS exposure, but also regulates the kinetics of apoptosis. A cis-acting motif within the N-terminal inhibitory domain of CED-8, as well as a transacting protein, CEI-1, (CED-8 Interaction protein) are both identified, and characterized. A further part of my Ph.D research aimed to decipher the mechanisms underlying the conserved process of paternal mitochondrial elimination (PME). In PME paternally derived mitochondria sacrifice themselves for the good of future progeny. Maternal inheritance of mitochondria is guaranteed through PME. Specifically, two pathways are characterized: first, the mitochondria localized nuclease, CPS-6 is activated to degrade the mitochondrial DNA during the process of PME; next, Parkin, a gene closely associated with familial Parkinsonʼs disease, plays a conserved role in regulating autophagy, which serves to quarantine paternal mitochondria. In my research, the Parkin homolog, PDR-1, was shown to flag paternal mitochondria for selective autophagic degradation. Loss of Parkin leads to non-selective enclosing of maternal organelles, obviously excluding paternal mitochondria. Moreover, the ubiquitination E3 ligase of Parkin is essential for Parkinʼs role in PME. This novel physiological role of Parkin thus provides novel and critical mechanistic insights into how Parkin deficiency may cause Parkinsonʼs disease.